November 14, 2022 Recent and Upcoming Diabetes Outcome Trials

Grace Leeder: Welcome everyone today to a Diabetes Canada Webinar about recent and upcoming diabetes outcome trials with Dr. Ronald Goldenberg. I'm very excited to have Dr. Goldenberg here speaking today on this topic. Dr. Ronald Goldenberg is a consultant endocrinologist affiliated with LMC Diabetes and Endocronoloy in Vaughan, Ontario. He completed his residency in internal medicine in 1987 at the University of Toronto and his fellowship in endocrinology and metabolism in 1989 at the University of Toronto. His major areas of interest include clinical care of diabetes. obesity, dyslipidemia and thyroid disorders. So, without furhter ado, I will pass it over to Dr. Goldberg.

Ronald Goldenberg: Well, thank you for the kind introduction, and thanks to Diabetes Canada for inviting me to present this webinar. Welcome all of you. There's been a lot of excitement with recent diabetes outcome trials over the past year, and there's a whole slew of ongoing diabetes outcome trials and what I would like to do today is to highlight some of the important recent outcome trials that potentially could change practice and highlight some ongoing trials that I think you'll all be interested in.

So these are my disclosures.

And the learning objectives for this webinar, and I hope that you'll be able to by the end of this session to discuss the results and clinical implications of key and recent diabetes outcome trials, and also to be able to review the design of ongoing diabetes of trials and what the key messages will be from those trials.

So for this webinar, I will actually focus on recent diabetes outcome trials which I define as being presented over the past year, and also focus on ongoing diabetes outcome trials. To qualify for review in this lecture I've included studies with patients that have diabetes, or at least a diabetes subgroup within these studies. And the primary outcome in the trials I will review has to have hard endpoints. So if it's a cardiovascular study, we’d have to have outcomes like CV death, MI, stroke or perhaps CV death or heart failure events. For kidney outcomes there has to be hard renal outcomes such as progressive loss of kidney function, end stage kidney disease or renal death, and for hepatic outcomes, serious liver outcome, such as cirrhosis or death related to liver disease or developing hepatocellular carcinoma.

So the outline for this talk is as follows: In the first section, I’ll focus on recent diabetes outcome trials that either have published or top-line data in 2022.  I'll review two important classes in this section. So SGL2 inhibitor trials and a trial with a Fibrate, and then the second part of the lecture will be for me to summarize ongoing diabetes outcome trials across a whole slew of different classes of medications.

So let's start with the recent diabetes outcome trials over this past year. Starting an SGLT2 inhibitor class and let’s start with the EMPULSE trial. So this was a trial that looked at the effect of Empagliflozin in patients hospitalized for acute heart failure. This is an important trial because the only other trial that looked at starting an SGLT2 inhibitor in hospital for heart failure patients was a trial with Sodogloflozin known as solo WHF. But of course Sodogloflozin is not available in Canada so I think clinicians would like to know can you start a currently available SGLT2 inhibitor in hospital patients with heart failure. So this trial basically took patients with acute heart failure, disregarding their ejection fraction, there were over 500 patients randomized in this trial, almost half of whom had type 2 diabetes and they were simply randomized Empagliflozin 10mg or placebo. The primary endpoint shown on the right of the slide was the clinical benefit evaluated with a win ratio across a composite of outcomes including death, number of heart failure events, time to first heart failure event and change from baseline in Kansas City Cardiomyopathy Questionnaire, Total Symptoms Score. With those of you who aren’t familiar with the win ratio, what they do is they take all possible pairs in the study of patients on study drug and patients on the placebo and they compare within each of these pairs in a hierarchical fashion each of the components of the primary outcome listed on the right of this slide. So for example, if you’re first pair, the patient on placebo died before the patient on Empagliflozin, that would be a win for Empagliflozin. If in that pair, none of the two individuals died during the study, they then go to the next outcome and look at number of heart failure events and if there were fewer heart failure events in the Empagliflozin arm compared to the placebo in that pair, then that would be a win for Empagliflozin. And they keep going through all the possible pairs across the hierarchy and count the number of wins in Empagliflozin and placebo and come up with a win ratio. And so that’s highlighted on this slide. And what you can see at the top of this slide for clinical benefit, 53.9% of these comparisons showed superiority with Empagliflozin, only 39.7% of the comparison were a win on the placebo. So that gives us stratified win ratio of 1.36 or you were 36% more likely to receive an overall clinical benefit with Empagliflozin compared to the placebo.

Below the top box on the slide you can see the individual outcomes, and generally Empagliflozin wins over placebo for each of these components of the primary outcome. So this is a nice way to do a trial, because you can get statistical significance without having to enroll 20,000 patients, and without having to follow patients for an extremely long period of time.

In this EMPULSE trial they look at predefined subgroups. There were about nine of them, and I just want to highlight that it didn't really matter which subgroup you looked at, Empagliflozin won over placebo so that applied whether you had de novo, heart failure, or decompensated chronic heart failure, and importantly for the purpose of this lecture It didn't matter whether or not you had diabetes, Empagliflozin was clearly better than placebo when looking at this win ratio. Furthermore, in other subgroups they included baseline left ventricular ejection fraction, so it really didn't matter if you had HFrEF (defined as a LV rejection factor of less than 40%) or heart failure with mild reduced or preserved ejection fraction, Emplagflozin was the winner.

The top line summary of the EMPULSE trial is Empagliflozin is that patients hospitalized for acute heart failure treated with Emplagflozin were 36% more likely to experience a clincal benefit. And this clinical benefit was consistent disregarding ejection fraction, disregarding whether this was new onset or a decompensated chronic heart failure, and importantly, whether or not the patients had type 2 diabetes. In this trial Emplagliflozin was well tolerated and the safety profile was as you would expect with an SGLT2 inhibitor. So here's another trial that shows that we should consider an SGLT2 inhibitor, in this case like Emplagliflozin for patients hospitalized with acute heart failure.

Another interesting heart failure trial that was presented and published at the European Society of Cardiology Meeting, just very recently, is the DELIVER trial. DELIVER trial is Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure. Here they included over 6,000 patients with heart failure with midly reduced or preserved ejection fraction. Almost half had type 2 diabetes. They were randomized to Dapagliflozin 10mg or placebo. The primary endpoint was basically the first occurrence of CV death for worsening heart failure events. And the major important result was the primary outcome here shown as an 18% relative risk reduction favouring Dapagliflozin and a number needed to treat, 32. So this follows on the trial with Emplagliflozin known as emperor preserve that also showed a benefit of a SGLT2 inhibitor in patients with hHF.

They looked at components of the primary endpoint and all individual components occurred less frequently in the Dapagliflozin group. You can see that CV death was not statistically significant but it probably was underpowered for see the CV death. In fact, if you include in a metanalysis, that HFrEF, dapaHF and the results of the DELIVER trial than CV death becomes statistically significant.

There are predefined subgroups in all these trials. Here's the subgroup analysis in DELIVER of about fourteen subgroups, and it really didn't matter which subgroup you look at but I just want to highlight in the red box, if you did or didn't have diabetes there was the same benefit with Dapagliflozin. In this trial overall, Dapagliflozin was safe and the adverse events were similar to placebo. And so the DELIVER trial now extends the benefit of Dapagliflozin and beyond HFrEF that we already knew in the DapaHF trial so we can now say that Dapagliflozin has been shown to benefit heart failure patients disregarding ejection fraction and whether or not you have diabetes.

The next trial I want to discuss is a trial called EMPA-KIDNEY. This is the first renal outcome trial with Empagliflozin and what they did is took a population of chronic kidney disease patients, with or without diabetes – about 6,600 patients, for most half of whom have diabetes – and basically randomized Empagliflozin 10mg or placebo. The primary endpoint being CV death or kidney disease.

 Now the inclusion criteria of this trial are a bit different than the renal outcome trials that we know with Canagliflozin, credence or Dapagliflozin, DapaCKD and highlighted on the left of the slide in bold font are the inclusion criteria based on GFR or ACR. And I just want to highlight there is a group here randomized with GFR <20 to <45 disregarding the ACR. This is the first renal outcome trial with a SGLT2 where you don’t necessarily have to have significantly elevated ACR.

Now as I speak to you today in this recorded broadcast, all I know about EMPA-KIDNEY that in March of 2022, the independent data monitoring committee recommends that the trial be stopped because of clear, positive efficacy in people randomized to Empagliflozin. By the time you see this, it will be presented at ASN Kidney Week and we will have more details about the overall results but now we have three positive outcome trials from a kidney point of view with SGLT2 inhibitors and EMPA-KIDNEY being  the third.

Now, the next trial, before I move on to ongoing out of trials is a trial with a Fibrate called Pemafibrate, which is actually not approved in Canada, called the prominence study. This is an important trial because the cardiovascular outcomes with fibrates on top of statins have been somewhat disappointing. So this trial was done in about 10,000 patients with type 2 diabetes. They have to be on a statin or statin intolerant with a good LDL and to get into the trial you have to have high triglycerides over .3 and an HDL of less than 1.0, very simply. These patients were randomized to the fibrate, Pemafibrate 0.2 mg or placebo and followed until over 1,000 primary mace outcomes were accumulated.

That's all we know about the prominent trial is in April of 2022, it was announced based on an interim analysis that the trial should be stopped because the primary endpoint was unlikely to be met meaning that Pemafibrate was probably neutral compared to Placebo.  And so at this point basically I would not prescribe a fibrate for cardiovascular protection in diabetes patients. We could use it for severe hypertryglderecemia to prevent pancreatitis but don't expect the cardiovascular benefits.

So in the remainder of the talk I just want to give a top line summary of some key ongoing diabetes outcome trials, and I'll do this by class. So we’ll talk about ongoing trials with GLP-1R agonists or so-called dual agonists, ongoing trials with SGLT2 inhibitors, I’ll mention one important trial with metformin. I’ll mention a couple of ongoing trials with PCSK9 type drugs. Also mineralocorticoid receptor antagonists and we’ll finally touch on a trial with an IL-6 ligand inhibitor.

So let’s go through the GLP-1 trials, the first of which is the FLOW trial. This is an important trial, because we already know that GLP-1s can reduce new onset macro albaneria, but we don't really know if they have a hard renal outcome benefit. So the FLOW trial is taking over 35,000 patients with type 2 diabetes and chronic kidney disease and they’re randomized to Semaglutide titrated up to 1mg once weekly or placebo. They’ll be followed up to 5 years and the primary outcome will be a composite of a 50% reduction in GFR, onset of a GFR less than 15, going on dialysis, having a renal or cardiovascular death. So we’ll know by August 2024 whether the GLP-1 receptor agonist provides a hard renal outcome benefit because thus far we don’t have hard renal data with GLP-1 reception agonists unlike we already know for SGLT2 inhibitors and we just talked about EMPA-KIDNEY.

There's another important trial with Semaglutide. This is the FOCUS trial. Many of you will recall that in the SUSTAIN six trials, Semaglutide was associated with worsening of retinopathy. Many experts believe that this was probably due to rapid glucose lowering, and if there was long term follow up, many suspect that there might be a retinopathy benefit, hence the rational of a FOCUS trial. So here's 1,500 patients with type 2 diabetes with various degrees of retinopathy randomized to Semaglutide or placebo. The primary outcome will be the presence of a greater than or equal to three step ETDRS score as a marker of retinopathy. This will be a very important trial because it's really going to be the first hard outcome trial looking at retinopathy with a GLP-1 receptor agonist.

So staying on the GLP-1 class there's a cardiovascular outcome trial with oral Semaglutide, called the SOUL trial. Here they're randomizing just less than 10,000 patients with type 2 diabetes and either established cardiovascular disease or kidney disease. They'll be randomized to oral semaglutide or a placebo and the primary endpoint will be your typical mace outcome of CV death, MI or stroke. And this is estimated to be finished by the summer of 2024.

Staying on the GLP-1 class, there's a lot of compelling information to suggest that GLP-1s may provide a benefit in patients with non-alcoholic steatle hepatitis. Hence the ESSENCE trial. This is enrolling patients with NASH with significant fibrosis. They may or may not have diabetes, and this trial has two important parts. Part one is just looking at a liver histology with important outcomes, such as resolution of NASH, and no worsening of fibrosis, or the improvement in fibrosis, and no worsening of NASH. But interestingly and this is somewhat unique in liver outcome trials, there's a part two where they're looking at the time to the first outcome of developing cirrhosis, dying, developing advanced liver induced what they call Meldscore, neeting a liver transparent or getting decompensation. This will be a definitive trial to show if the GLP-1 semaglutide at a high dose of 2.4mg provides a liver benefit but in NASH.

Now, as you all know, in the pipeline are the GLP-1 receptor coagonists, the first one that will come to Canada is through Tirzepatide. This is a GLP-1 GIP dual agnoist, and there is an ongoing cardiovascular outcome trial with this agent where patients are titrated to tirzepatide 15mg once a week and the comparator is dulaglutide, which we already know from the REWIND trial provides a cardiovascular benefit. We already know that tirzepatide has robust A1C lowering and robust weight loss but this will be the definitive cardiovascular outcome trial with this agent and we should have results by October of 2024.

 Staying on the dual agonist theme, there's a trial with HFpEF with tirzepatide. To get into this trial, you have to have an LV ejection fraction of 50% or more. You may or may not have diabetes, and they're randomized to tirzepatide or placebo, and similar to the EMPULSE trial, the primary outcome will look at a win ratio based on a composite of all cause death, heart failure events, a six minute walking distance test, the Kansas City Cardiomyopic Questionnaire test score and there’s also a secondary outcome just looking at the change in the six minute walking test. So there's a lot of data to suggest that patients with HFpEF may benefit from robust weight loss and tirzepatide may help answer this question in the summit HFpEF trial.

Staying... going back to SGLT2 inhibitors and ongoing trials, there is a trial with dapagliflozin from the TIMI group called DAPA ACT HF-TIMI 68. Kind of similar to the EMPULSE trial, this is looking at patients with acute heart failure but in this case randomized to Dapagliflozin and placebo. It’s a pretty large trial, 24,000 patients and it will look at a primary outcome of CV death or worsening heart failure and we’ll know the results of this by February of 2023.

The other question about SGLT2 inhibitors is we don't really know their benefit if administered right after an acute mild infarction because the previous trials with patients with as ASCVD had stable ASCVD so this is the EMPACT-MI trial. 5,000 patients within two weeks of NSTEMI or STEMI without type 2 diabetes and basically Empagliflozin or placebo and they are looking at a primary outcome of a composite of heart failure or all cause mortality. And this is estimated to be completed by the end of this year, so 2023 we should hear about the results of the EMPACT-MI trial.

This next trial is not a diabetes outcome for all but I thought it was important because it's a pre-diabetes outcome trial looking at metformin. Because meftormin, it’s somewhat cotnroversial whether it has a  cardiovascular benefit they design the VA-IMPACT trial looking at cardiovascular outcomes with metformin in patients with pre diabetes. So basically 7,400 patients who have ASCVD and pre-diabetes will be randomized to extended release meformin or placebo. They’ll be followed for almost five years and they’ll be looking at a primary outcome of death, MI, stroke, hospitalization for unstable angina or a coronary revascularization. Really, this will be a definition cardiovascular outcome trial for metformin in a pre-diabetes population. But we have to wait until roughly September 2028 for this.

Now all of us have started to use PSCK9 inhibitors over recent years because of the Fourier trial with Evolocumab and the ODDYSSEY outcome trial with Alirocumab. Now, Fourier used Evolocumab but to get into that trial you had to have a prior MI or stroke. And so this is a new trial with Evolocumab called the VESALIUS-CV trial. To get into this trial, you have to be at high risk of CV events but didn’t have a prior MI or stroke. So the 12,000 patients in this trial will get in if they have established CAD but haven’t had an MI, Established cerebral vascular disease but haven’t had a stroke. They can have PAD and importantly they can have diabetes with at least another additional high risk feature. These patients will already be on statin, with or without ezetimibe. They will be randomized to evolocumab or placebo. After about 4 years or more of follow-up, they’ll have a primary MACE outcome and if positive, this would obviously expand the use of evolocumab who are at high risk but have not necessarily had a cardiovascular event and importantly a big chunk of patients with diabetes without prior MI or stroke are in this trial.

Now there is a PCSK9 interfering MRNA approved in Canada but not yet launched and I suspect that by late this year or 2023, we will be able to prescribe Inclisiran. Basically, this is a cardiovascular outcome trial with Inclisiran called ORION-4. It’s a secondary prevention trial. Patients already on background statin therapy are randomized to Inclisiran versus placebo. Very simple drug to prescribe because you get the first dose, then a follow-up dose at 3 months and then every 6 months by subcutaneous injection. This trial you can have or not have type 2 diabetes but amongst the 15,000 patients, we suspect many will have diabetes and they’ll be followed for 4-5 years until about July 2026 looking at a primary endpoint of CHD death, MI, stroke or urgent coronary revascularization.

I'll shift gears very briefly show you trials with the minarella cordiquated receptor agonist class looking at HFpEF. So HFpEF is very common in obesity and diabetes and there's a lot of interest in finding agents beside SGLT2 inhibitors that provide a benefit in HFpEF. One of the classes of great interest are the MR antagonists. So there's two ongoing trials with spironolcatone, SPIRIT-HF and SPIRRIT and an ongoing trial with a non-steroidal MR antagonist called finerenone called FINEARTS-HF trial. Finerenone is just being launched in Canada and will be approved for patients with type 2 diabetes and chronic kidney disease and the FINEARTS trial will answer the question, is finerenone provide a benefit in HFpEF patients. And importantly, each of these trials will include patients with diabetes.

Finally and importantly, the last trial I want review with you is with a yet to be approved interlucan 6 ligand inhibitor called ziltivekimab. Ziltivekimab provides antiinflammatory effects by targeting interlucan 6 and the ZEUS trial shown here is a cardiovascular outcome trial in over 6,000 patients with ASCVD, CKD and elevated hsCRP as a marker of inflammation and you can get into this trial if you have diabetes with an A1C below 10%. These patients will be randomized to ziltivekimab or placebo. The trial will completely in roughly 2025 and is looking at a primary MACE outcome.

So thank you for your attention that is all I had to say today. So this was a quick review of key completed outcome trial sin diabetes in the last year and the view into a future of what you can look forward to over the coming few years in the future for diabetes outcome trials. So thank you for your attention and thank you for listening to me today.

Grace Leeder: Thank you so much Dr. Goldenberg. What a wonderful presentation. We would love folks to provide us feedback on today’s webinar. You can do so by scanning the QR code and filling out a brief survey and we very much appreciate your feedback.

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Thank you for watching, more webinars and podcasts are available at www.diabetes.ca/health-care-providers. Thank you so much to Dr. Goldenberg for presenting today on this wonderful topic and we will see you in the future.